Cancer Vaccines: Contemporary Approach of Cancer Treatment

Abstract

Adaptive immunotherapy or vaccines has been tried as a therapeutic option against cancer in the past decade. It is necessary for patients in advanced stage malignancy to have an efficient treatment. By taking in consideration that cancer vaccines are presenting effective results primarily in prophylactic settings, it is significant to develop therapeutic vaccines against cancer. On the contrary to the infectious diseases, cancers ascends from own body cells, to which immune system gets tolerized. Hence, to develop active immune response against cancer is more challenging compared to the infectious diseases.

Keywords

Cancer, Cancer vaccines, Oncolytic viruses, Dendritic cells

Modes of Cancer Treatment

Cancer can be defined as uncontrolled cell proliferation where non- characterized cells have ability to colonies in adjacent body parts [1-8]. Cancer which originates in breast tissue or other related part is called as breast cancer [8-19]. It is the most common type of cancer found in India and according to recent statistics, breast cancer accounts for 27% of overall cancers in women in India. As per the data, there are 1, 44,937 cases register of breast cancer and 70,218 deaths were reported. Hence, by following these numbers we can state that success rate of cancer treatment is very poor [20-32].

Current cancer treatment includes mainly three aspects: Surgery–where the specific cancer causing tissue or tumor is removed, Chemotherapy–where different drugs are given to reduce the tumor growth and Radiotherapy–where radiation is used to control metastatic tumor [33-41]. Even though these treatments are being used widely, there is necessity of new treatment methods due to high mortality rate. The following Figureshows increase in breast cancer cases in India in 2015 compared to last 25 years [42-51].

Figure 1: Comparison of breast cancers in India presently and before 25 years.

The modern approach in cancer treatment includes many different methods where cancer vaccines, use of m-RNA and Nano drugs are showing very promising results and it can be considered as the future of cancer treatment [52-59].

Cancer Vaccine

Cancer vaccines or therapeutic cancer vaccines are the newer attempt to treat cancer, where it is used to treat existing cancer or to avoid development of cancer [60-69]. Research is going on cancer vaccines mainly against breast, lung, colon, skin, kidney and prostate cancers [70].

There are different approaches of mechanism of cancer vaccines. One style is to separate proteins from cancer cells and to immunize patients against those proteins. These proteins act as the antigens and stimulate the immune system to kill cancer cells [71-76]. Another method involves generation of an immune response in patients by using oncolytic viruses. This is considered as the better option as it provides ‘patient specific vaccine’ where viruses are engineered to selectively replicate in tumor tissue hence they can express the immune stimulatory protein [77-79]. Basically cancer vaccines work by delivering target antigen to dendritic cells. These cells exist in antigen processing site. Dendritic cells get activated by adjuvants which are present in the vaccines [80-83]. Immune system reacts to this by increasing number of T-cells and transferring to lymph node. Followed by this, activated DCs provide antigen to T-cells; which identifies its associated antigen and gets activated [84]. This allows production of cytokines from CD4+ cells which triggers full maturation of CDT cells. Subsequently CD8+ multiplies and circulates extensively all over the body [85-87]. When a cell containing target antigen of this activated T-cell comes in range, it results in lysis of that cell which gives antitumor response (Figure 2). Currently cervical, oropharyngeal cancer (against HPV) and liver cancer vaccines (against Hepatitis B virus) are approved in the world [88,89].

Figure 2. Major features of cancer vaccines.

Figure 2: Major features of cancer vaccines.

Conclusion

Hence, in conclusion, cancer vaccines are emerging as long lasting, appealing method for antitumor immunity [90]. As first anti-tumor cancer vaccine has got approval, it will give next generation of vaccines with improved antitumor action which can be used for the patients who are having high risk of recurrence. Improved research on host-tumor interactions and tumor immune escape mechanisms is required for conversion of cancer vaccines into clinically accessible medications with wide range of applications [91-93]. The cancer vaccine therapy can also be improvised by recognition of distinctive tumor gene or protein product which causes alteration of normal cells into tumor cells and leads to cancer progression. Better quality clinical outcomes can be obtained by blending vaccine strategies with supplementary mediators which synergistically add to antitumor immunity [94-100].

References

1. Shields CL, et al. Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Arch. Ophthalmol. 2000;118:1497-1507.
2. Ferry AP and Font R. Carcinoma metastatic to the eye and orbit I. A clinicopathologic study of 227 cases. Arch Ophthalmol. 1974;92:276-86.
3. Volpe NJ and Albert DM. Metastasis to the uvea. In: Albert DM, Jakobiec FA, editors. Principles and practice of ophthalmology. Philadelphia: WB Saunders. 1994;3260-70.
4. Merril CF, et al. Breast cancer metastatic to the eye is a common entity. Cancer. 1991;68:623-627.
5. Fenton S, et al. Screening for ophthalmic involvement in asymptomatic patients with metastatic breast carcinoma. Eye. 2004;18:38-40.
6. Dobrowsky W. Treatment of choroid metastases. Br J Radiol. 1988;61:140-142.
7. Aragão RE, et al. Choroidal metastasis as the first sign of bronchioloalveolar lung cancer: case report. Arq Bras Oftalmol. 2013;76:250-252.
8. Sánchez R, et al. Choroidal metastasis as first manifestation of systemic recurrence of breast cancer. Breast J. 2008;14:498-500.
9. Eide N, et al. Fine needle aspiration biopsy in selecting treatment for inconclusive intraocular disease. ActaOphthalmol. Scand. 1999;77:448-452.
10. O'Connell TM. Recent advances in metabolomics in oncology. Bioanalysis. 2012;4:431-451.
11. Singletary SE, et al. Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol. 2002;20:3628-3636.
12. Louis E, et al. Phenotyping human blood plasma by 1H-NMR: a robust protocol based on metabolite spiking and its evaluation in breast cancer. Metabolomics. 2015;11:225-236.
13. Ascierto ML, et al. A signature of immune function genes associated with recurrence-free survival in breast cancer patients. Breast Cancer Res Treat. 2011
14. Diaz-Montero CM, et al. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicincyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009;58:49-59.
15. Morales JK, et al. GMCSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1- bone marrow progenitor cells into myeloidderived suppressor cells. Breast Cancer Res Treat. 2010;123:39-49.
16. Morales JK, et al. Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells. Cancer Immunol Immunother. 2009; 58:941-953.
17. Ciampricotti M, et al. Development of metastatic HER2+ breast cancer is independent of the adaptive immune system. J Pathol. 2011;224:56-66.
18. Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis. J ClinPharmacol. 2005;45:872-877.
19. Jordan CT. Cancer stem cells: controversial or just misunderstood? Cell Stem Cell. 2009;4:203-205.
20. Liu TC and Kirn D. Gene therapy progress and prospects cancer: oncolytic viruses. Gene Ther. 2008;15:877-884.
21. Islam MO, et al. Functional expression of ABCG2 transporter in human neural progenitor cells. Neurosci Res. 2005; 52:75.
22. Aghi M, et al. Effect of chemotherapy-induced DNA repair on oncolytic herpes simplex viral replication. J Natl Cancer Inst. 2006;98:38-50.
23. Kelly E and Russell SJ. History of oncolytic viruses: genesis to genetic engineering. MolTher. 2007;15:651-659.
24. Redding N, et al. The utility of oncolytic viruses against neuroblastoma. In The 5th International Meeting on Replicating Oncolytic Virus Therapeutics, Banff, Canada. 2009.
25. Lichty BD, et al. Vesicular stomatitis virus: re-inventing the bullet. Trends Mol Med. 2004;10:210-216.
26. Liu TC, et al. Clinical trial results with oncolyticvirotherapy: a century of promise, a decade of progress. Nat ClinPractOncol. 2007;4:101-117.
27. Mullen JT and Tanabe KK. Viral oncolysis. Oncologist. 2002;7:106-119.
28. Ponti D, et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 2005;65:5506-5511.
29. Alain T, et al. Reovirus therapy of lymphoid malignancies. Blood. 2002;100:4146-4153.
30. Yap TA, et al. Reovirus therapy in cancer: has the orphan virus found a home. Expert OpinInvestig Drugs. 2008;17:1925-1935.
31. Marcato P, et al. Oncolyticreovirus effectively targets breast cancer stem cells. MolTher. 2009;17:972-979.
32. Steinman RM and Witmer MD. Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice. ProcNatlAcadSci U S A. 1978;75:5132-5136.
33. Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271-296.
34. Schraml BU and Reis e Sousa C2. Defining dendritic cells. CurrOpinImmunol. 2015;32:13-20.
35. Alvarez D, et al. Mechanisms and consequences of dendritic cell migration. Immunity. 2008;29:325-342.
36. Plato A, et al. C-type lectin-like receptors of the dectin-1 cluster: ligands and signaling pathways. Int Rev Immunol. 2013;32:134-156.
37. Probst HC, et al. Regulation of the tolerogenic function of steady-state DCs. Eur J Immunol. 2014;44:927-933.
38. Crietman TO, et al. Innate immune memory: Implications for host responses to damage-associated molecular patterns. Eur J Immunol. 2016;46:817-828.
39. Steinman RM and Idoyaga J. Features of the dendritic cell lineage. Immunol Rev. 2010;234:5-17.
40. Liu J and Cao X. Regulatory dendritic cells in autoimmunity: A comprehensive review. J Autoimmun. 2015;63:1-12.
41. Matzinger P. The danger model: a renewed sense of self. Science. 2002;296:301-305.
42. Zhang JG, et al. The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments. Immunity. 2012;36:646-657.
43. Pizzurro GA and Barrio MM. Dendritic cell-based vaccine efficacy: aiming for hot spots. Front Immunol. 2015;6:91.
44. Sallusto F, et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol. 1998;28:2760-2769.
45. Chen Z. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005;436: 725-730.
46. Stumbles PA, et al. Regulation of dendritic cell recruitment into resting and inflamed airway epithelium: use of alternative chemokine receptors as a function of inducing stimulus. J Immunol. 2001;167:228-234.
47. Johnson LA and Jackson DG. Control of dendritic cell trafficking in lymphatics by chemokines. Angiogenesis. 2014;17:335-345.
48. MartIn-Fontecha A, et al. Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med. 2003;198:615-621.
49. Hauser MA and Legler DF. Common and biased signaling pathways of the chemokine receptor CCR7 elicited by its ligands CCL19 and CCL21 in leukocytes. J LeukocBiol. 2016;99:869-882.
50. Kim SH, et al. Recruitment of Rab27a to phagosomes controls microbial antigen cross-presentation by dendritic cells. Infect Immun. 2008;76:5373-5380.
51. Doherty PC and Zinkernagel RM. H-2 compatibility is required for T-cell-mediated lysis of target cells infected with lymphocytic choriomeningitis virus. J Exp Med. 1975;141:502-507.
52. Bevan MJ. Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay. J Exp Med. 2010;143:1283-1288.
53. Saab R. Cellular senescence: many roads, one final destination. ScientificWorldJournal. 2010;10:727-741.
54. Hayflick L and Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585-621.
55. Sharpless NE and Sherr CJ. Forging a signature of in vivo senescence. Nat Rev Cancer. 2015;15:397-408.
56. Kuilman T and Peeper DS. Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer. 2009;9: 81-94.
57. Coppe JP. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118.
58. Acosta JC and Gil J. Senescence: A new weapon for cancer therapy. Trends Cell Biol. 2012;22:211-219.
59. Salama R. Cellular senescence and its effector programs. Genes Dev. 2014;28:99-114.
60. Kuilman T. The essence of senescence. Genes Dev. 2010;24:2463-2479.
61. Nardella C. Pro-senescence therapy for cancer treatment. Nat Rev Cancer. 2011;11:503-511.
62. Frederick MJ. Phosphoproteomic analysis of signaling pathways in head and neck squamous cell carcinoma patient samples. Am J Pathol. 2011;178:548-571.
63. Munoz-Espin D and Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014; 15:482-496.
64. Serrano M. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88:593-602.
65. Braig M. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature. 2005;436:660-665.
66. Collado M. Tumour biology: Senescence in premalignant tumours. Nature. 2005;436:642.
67. Lazzerini Denchi E. Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland. Mol Cell Biol. 2005;25:2660-2672.
68. Michaloglou C. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436:720-724.
69. Quintanilla M. Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature. 1986;322:78-80.
70. Bennecke M. Ink4a/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis. Cancer Cell. 2010;18:135-146.
71. Courtois-Cox S. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 2006;10:459-472.
72. Shamma A. Rb Regulates DNA damage response and cellular senescence through E2F-dependent suppression of N-ras isoprenylation. Cancer Cell. 2009;15:255-269.
73. Young AP. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat Cell Biol. 2008;10:361-369.
74. Hart DN. Dendritic cells: unique leukocyte populations which control the primary immune response. Blood. 1997;90:3245–3287.
75. Caux C, et al. GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature. 1992;360:258–261.
76. Inaba K, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med. 1992;176:1693–1702.
77. Sallusto F and Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994;179:1109–1118.
78. Steinman RM, et al. Tolerogenic dendritic cells. Annu Rev Immunol.2003;21:685–711.
79. Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol. 2005;23:275–306.
80. Ginhoux F, et al. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J Exp Med. 2007;204:3133–3146.
81. Poulin LF, et al. The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells. J Exp Med.2007;204:3119–3131.
82. Randolph GJ, et al. Migration of dendritic cell subsets and their precursors. Annu Rev Immunol. 2008;26:293–316.
83. Bujdoso R, et al. Characterization of sheep afferent lymph dendritic cells and their role in antigen carriage. J Exp Med. 1989;170:1285–1301.
84. Iijima N, et al. Vaginal epithelial dendritic cells renew from bone marrow precursors. Proc Natl Acad Sci U S A. 2007;104:19061–19066.
85. Holt PG, et al. Origin and steady-state turnover of class II MHC-bearing dendritic cells in the epithelium of the conducting airways. J Immunol. 1994;153:256–261.
86. Pugh CW, et al. Characterization of nonlymphoid cells derived from rat peripheral lymph. J Exp Med. 1983;157:1758–1779.
87. Merad M, et al. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat Rev Immunol. 2008;8:935–947.
88. Merad M, et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol. 2002;3:1135–1141.
89. Collin MP, et al. The fate of human Langerhans cells in hematopoietic stem cell transplantation. J Exp Med. 2006;203:27–33.
90. Kanitakis J, et al. Turnover of epidermal Langerhans' cells. N Engl J Med. 2004;351:2661–2662.
91. Shortman K and Liu YJ. Mouse and human dendritic cell subtypes. Nat Rev Immunol. 2002;2002:151–161.
92. den Haan JM, et al. CD8(+) but not CD8(-) dendritic cells cross-prime cytotoxic T cells in vivo. J Exp Med. 2000;192:1685–1696.
93. Kabashima K, et al. Intrinsic lymphotoxin-beta receptor requirement for homeostasis of lymphoid tissue dendritic cells. Immunity. 2005;22:439–450.
94. Liu K, et al. Origin of dendritic cells in peripheral lymphoid organs of mice. Nat Immunol. 2007;8:578–583.
95. Manz MG, et al. Dendritic cell potentials of early lymphoid and myeloid progenitors. Blood. 2001;97:3333–3341.
96. Traver D, et al. Development of CD8 alpha-positive dendritic cells from a common myeloid progenitor. Science. 2000;290:2152–2154.
97. Iwasaki A. Mucosal dendritic cells. Annu Rev Immunol. 2007;25:381–418.
98. Wu L and Shortman K. Heterogeneity of thymic dendritic cells. Semin Immunol. 2005;17:304–312.
99. Brocker T, et al. Targeted expression of major histocompatibility complex (MHC) class II molecules demonstrates that dendritic cells can induce negative but not positive selection of thymocytes in vivo. J Exp Med. 1997;185:541–550.
100. Donskoy E and Goldschneider I. Two developmentally distinct populations of dendritic cells inhabit the adult mouse thymus: demonstration by differential importation of hematogenous precursors under steady state conditions. J Immunol. 2003;170:3514–3521.